Use of stannylenes and germylenes as polymerization catalysts for heterocycles

ABSTRACT

The use of stannylenes and germylenes of general formula (I) wherein: M represents a tin or geranium atom; L 1  and L 2  independently represent a group of formula: -E 14 (R 14 ) (R′ 14 ) (R″ 14 ), -E 15 (R 15 ) (R′ 15 ) or -E 16 (R 16 )) or together form a chain of formula -L′ 1 -A- L′ 2 ; A represents a saturated or unsaturated chain comprising one, two or three elements of group 14; L′ 1  and L′ 2 , represent, independently, a group of formula: -E 14 (R 14 ) (R′ 14 )-, E 15 (R 15 )- or -E 16 -; E 14  is an element of group 14; E 15  is an element of group 15; E 16  is an element of group 16; R 14 , R′ 14 , R″ 14 , R 15 , R′ 15  and R 16  represent variable groups as polymerization catalysts of heterocycles.

This application is a 371 of PCT/FR01/01405 filed May 10, 2001.

The present invention relates to the use of stannylenes and germylenesas polymerization catalysts of heterocycles.

It has been demonstrated that each type of catalyst used for thepolymerization or copolymerization of heterocycles, respectivelyproduces different polymers or copolymers, in particular as a result ofredistribution reactions [Jedlinski et al., Macromolecules, (1990) 191,2287; Munson et al., Macromolecules, (1996) 29, 8844; Montaudo et al.,Macromolecules, (1996) 29, 6461]. The problem is therefore finding newcatalytic systems in order to obtain new polymers or copolymers.

Moreover, the catalytic systems allowing block copolymers to be obtainedare of particular interest. In fact, the sequence of monomers can, inthis case, be controlled in order to obtain specific copolymers havingspecific properties. This is particularly useful for biocompatiblecopolymers, the biodegradation of which is influenced by this sequence.

A subject of the present invention is therefore the use of stannylenesand germylenes of general formula 1

in which

-   -   M represents a tin or germanium atom;    -   L₁ and L₂ represent, independently, a group of formula        -E₁₄(R₁₄)(R′₁₄)(R″₁₄), -E₁₅(R₁₅)(R′₁₅) or -E₁₆(R₁₆), or together        form a chain of formula -L′₁-A-L′₂-;    -   A represents a saturated or unsaturated chain comprising one,        two or three elements of group 14, each being optionally and        independently substituted by one of the following substituted        (by one or more identical or different substituents) or        non-substituted radicals: alkyl, cycloalkyl, aryl, in which said        substituent is a halogen atom, the alkyl, aryl, nitro or cyano        radical;    -   L′₁ and L′₂ represent, independently, a group of formula        -E₁₄(R₁₄)(R′₁₄)-, -E₁₅(R₁₅)- or -E₁₆-;    -   E₁₄ is an element of group 14;    -   E₁₅ is an element of group 15;    -   E₁₆ is an element of group 16;    -   R₁₄, R′₁₄, R″₁₄, R₁₅, R′₁₅ and R₁₆ represent, independently, the        hydrogen atom;    -   one of the following substituted (by one or more identical or        different substituents) or non-substituted radicals:alkyl,        cycloalkyl or aryl, in which said substituent is a halogen atom,        the alkyl, cycloalkyl, aryl, nitro or cyano radical; a radical        of formula -E′₁₄RR′R″;    -   E′₁₄ is an element of group 14;    -   R, R′ and R″ represent, independently, the hydrogen atom or one        of the following substituted (by one or more identical or        different substituents) or non-substituted radicals:alkyl,        cycloalkyl, aryl, in which said substituent is a halogen atom,        the alkyl, aryl, nitro or cyano radical;        as polymerization catalysts of heterocycles.

In the definitions indicated above, the expression halogen represents afluorine, chlorine, bromine or iodine atom, preferably chlorine. Theexpression alkyl preferably represents a linear or branched alkylradical having 1 to 6 carbon atoms and in particular an alkyl radicalhaving 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl radicals.

The cycloalkyl radicals are chosen from saturated or unsaturatedmonocyclic cycloalkyls. The saturated monocyclic cycloalkyl radicals canbe chosen from radicals having 3 to 7 carbon atoms such as thecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptylradicals. The unsaturated cycloalkyl radicals can be chosen from thecyclobutene, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadieneradicals.

The aryl radicals can be of mono or polycyclic type. The monocyclic arylradicals can be chosen from the phenyl radicals optionally substitutedby one or more alkyl radicals such as tolyl, xylyl, mesityl, cumenyl.The polycyclic aryl radicals can be chosen from the naphthyl, anthryl,phenanthryl radicals.

The compounds of formula 1 can be presented in the form of monomers orof dimers, the dimers being able to adopt a linear or cyclic structure[C. Glidewell Chem. Scripta (1987) 27, 437]. Thus, the compounds offormula 1 can be presented, when L₁ and L₂ are independent, in thefollowing forms:

and, when L₁ and L₂ together form an -L′₁-A-L′₂-chain, in the followingforms:

The compounds of formula 1 can comprise one or more solvent molecules[stannylene-tetrahydrofuran complexes were detected spectroscopically:W. P. Neumann Chem. Rev. (1991) 91, 311]. The expression solventrepresents an aromatic hydrocarbon such as benzene, toluene; a cyclic oracyclic dialkyl ether such as diethylether, dioxane, tetrahydrofuran,ethyl tertbutyl ether; a chlorinated solvent such as dichloromethane,chloroform; an aliphatic or aromatic nitrile such as acetonitrile,benzonitrile; a cyclic or acyclic, aliphatic or aromatic ketone, such asacetone, acetophenone, cyclohexanone; a cyclic or acyclic, aliphatic oraromatic derivative of carboxylic acid such as ethyl acetate,dimethylformamide.

A more particular subject of the invention is the use as polymerizationcatalysts of heterocycles, of the products of general formula 1 asdefined above, characterized in that M represents a tin atom.

A more particular subject of the invention is also the use aspolymerization catalysts of heterocycles, of the products of generalformula 1 as defined above, characterized in that L₁ and L₂ represent,independently, a group of formula -E₁₄(R₁₄)(R′₁₄)(R″₁₄), -E₁₅(R₁₅)(R′₁₅)or -E₁₆(R₁₆).

Preferably, the use as defined above of a compound of formula 1 is suchthat

-   -   E₁₄ is a carbon or silicon atom;    -   E₁₅ is a nitrogen or phosphorus atom;    -   E₁₆ is an oxygen or sulphur atom;    -   R₁₄, R′₁₄, R″₁₄, R₁₅, R′₁₅ and R₁₆ represent, independently, the        hydrogen atom, an alkyl radical or a radical of formula        -E′₁₄RR′R″;    -   E′₁₄ is a carbon or silicon atom;    -   R, R′ and R″ represent, independently, the hydrogen atom or an        alkyl radical.

Preferably also, the use as defined above of a compound of formula 1 issuch that

-   -   L₁ and L₂ represent, independently, a group of formula        -E₁₅(R₁₅)(R′₁₅) or -E₁₆(R₁₆);    -   E₁₅ is a nitrogen atom;    -   E₁₆ is an oxygen atom;    -   R₁₅ and R′₁₅ independently represent an alkyl radical or a        radical of formula -E′₁₄RR′R″;    -   R₁₆ represents an alkyl radical;    -   E′₁₄ represents a silicon atom;    -   R, R′and R″represent, independently, the hydrogen atom or an        alkyl radical.

Preferentially, the compound of formula 1 as defined above, correspondsto one of the following formulae:

-   -   -[(Me₃Si)₂N]₂Sn;    -   -{[(Me₃Si)₂N]Sn(Ot-Bu)}₂.

Certain compounds of formula 1 are known products, i.e. the synthesisand characterization of which have been described [M. F. Lappert et al.,J. Chem. Soc., Chem. Commun. (1973), 317; J. J. Zuckerman et al., J. Am.Chem. Soc. (1974) 96, 7160; M. F. Lappert et al., J. Chem. Soc., Chem.Commun. (1974) 895; M. Veith, Angew. Chem., Int. Ed. Engl. (1975) 14,263; M. F. Lappert et al., J. Chem. Soc., Dalton Trans (1976), 2268; M.F. Lappert et al., J. Chem. Soc., Dalton Trans. (1977), 2004; M. Veith,Z. Naturforsch (1978) 33b, 1; ibid (1978) 33b, 7; M. F. Lappert et al.,J. Chem. Soc., Chem. Commun., (1983) 639; ibid (1983) 1492; ibid (1992)1311; M. F. Lappert et al., J. Am. Chem. Soc, (1980) 102, 2088]. As aresult, the new compounds of formula 1 can be prepared by analogyaccording to the synthesis routes already described.

Moreover, certain compounds of formula 1 have been used in heterocyclepolymerization (thioepoxides) [S. Kobayashi et al., Makromol. Chem.,Macromol. Symp. (1992) 54/55, 225]. But in this case, they both play therole of comonomer and polymerization initiator (oxidation-reductioncopolymerization) and are then stoichiometrically incorporated into thepolymerization products. They therefore do not play the role of acatalyst.

The invention relates to the use of products of formula 1 as definedabove, as catalysts for the implementation of the (co)polymerization ofheterocycles, i.e. polymerization or copolymerization of heterocycles.During the implementation of the (co)polymerization, the compoundsaccording to the invention also play the role of chain initiator orregulator, but are not stoichiometrically incorporated into the(co)polymers.

The heterocycles can contain one or more heteroatoms of groups 15 and/or16, and be of a size ranging from three to eight members. As examples ofheterocycles corresponding to the above formulation, there can bementioned epoxides, thioepoxides, cyclic thioesters or esters such aslactones, lactames and anhydrides.

The compounds of formula 1 are particularly useful for theimplementation of the (co)polymerization of epoxides, in particular ofpropene oxide. The compounds of formula 1 are also particularly usefulfor the implementation of the (co)polymerization of cyclic esters. Asexamples of cyclic esters, there can be mentioned the cyclic esterpolymers of lactic and/or glycolic acid. Random or block copolymers canbe obtained depending on whether the monomers are introduced together atthe beginning of the reaction, or sequentially during the reaction.

A subject of the invention is also a process for the preparation ofcopolymers, block or random, or polymers and which consists ofintroducing one or more monomers, a chain initiator, a polymerizationcatalyst and optionally a polymerization solvent, said processcharacterized in that the chain initiator and the polymerizationcatalyst are represented by the same compound which is chosen from thecompounds of formula 1 as defined above.

The (co)polymerization can be carried out either in a solution or bysupercooling. When the (co)polymerization is carried out in solution,the reaction solvent can be the (or one of the) substrate(s) used in thecatalytic reaction. Solvents which do not interfere with the catalyticreaction itself are also suitable. As examples of such solvents, therecan be mentioned saturated or aromatic hydrocarbons, ethers, aliphaticor aromatic halides.

The reactions are carried out at temperatures comprised between ambienttemperature and approximately 250° C.; the temperature range comprisedbetween 40 and 200° C. being more advantageous. The reaction times arecomprised between a few minutes and 300 hours, and preferably between 5minutes and 72 hours.

This (co)polymerization process is particularly suitable for obtainingcyclic ester (co)polymers, in particular the cyclic ester polymers oflactic and/or glycolic acid. The products obtained such as lacticglycolic copolymer, which are biodegradable, are advantageously used assupports in sustained release therapeutic compositions. The process isalso particularly suited to the polymerization of epoxides, inparticular propene oxide. The polymers obtained are compounds which canbe used for the synthesis of organic liquid crystals or also assemi-permeable membranes.

The process for the (co)polymerization of heterocycles according to thepresent invention, has numerous advantages, in particular,

-   -   (co)polymerization catalysts are easily accessible and cheap    -   (co)polymerization can really be carried out in a homogeneous        medium so that the mass distribution of the (co)polymers        obtained is narrow;    -   the process is particularly suited to the preparation of block        copolymers; the successive addition of monomers in particular        allows copolymers to be obtained in blocks.

The invention finally relates to polymers or copolymers which may beobtained by the implementation of a process as described above.

Unless they are defined otherwise, all the technical and scientificterms used in the present application, have the same meaning as thatusually understood by an ordinary specialist of the field to which theinvention belongs. Similarly, all the publications, patent applicationsand all other references mentioned in the present application, areincorporated by way of reference.

The following examples are presented in order to illustrate the aboveprocedures and should in no event be considered as a limit to the scopeof the invention.

EXAMPLE 1 Preparation of a Random (D,L-lactide/glycolide) Copolymerhaving a Lactide/glycolide Composition Close to 75/25

0.023 g (0.05 mmol) of [(Me₃Si)₂N]₂Sn, 5.66 g (39.3 mmol) ofD,L-lactide, 1.52 g (13.1 mmol) of glycolide and 15 ml of mesitylene areintroduced successively into a Schlenk tube equipped with a magneticstirrer and purged under argon. The reaction mixture is left understirring at 160° C. for 3 hours. NMR analysis of the proton allowsverification that the conversion of each of the monomers (lactide andglycolide) is 100%. The ratio of the signal integrals corresponding tothe polylactide part (5.20 ppm) and polyglycolide part (4.85 ppm) allowsthe composition of the copolymer to be evaluated at 75% lactide and 25%glycolide. According to GPC analysis, using a calibration carried outfrom PS standards with masses 761 to 400 000, this copolymer is amixture of macromolecules (Mw/Mn=1.67) with quite high masses (Mw=77 500Dalton).

EXAMPLE 2 Preparation of a Random (D,L-lactide/glycolide) Copolymer withHigh Masses

0.023 g (0.05 mmol) of [(Me₃Si)₂N]₂Sn, 6.03 g (41.9 mmol) of D,L-lactideand 2.08 g (17.9 mmol) of glycolide are introduced successively into aSchlenk tube equipped with a magnetic stirrer and purged under argon.The reaction mixture is left under stirring at 140° C. for 10 minutes.NMR analysis of the proton allows verification that the conversion ofthe monomers is 83% for the lactide and 100% for the glycolide. Theratio of the signal integrals corresponding to the polylactide part(5.20 ppm) and polyglycolide part (4.85 ppm) allows the composition ofthe copolymer to be evaluated at 70% lactide and 30% glycolide.According to GPC analysis, using a calibration carried out from PSstandards with masses 761 to 400 000, this copolymer is a mixture ofmacromolecules (Mw/Mn =1.8) of high masses (Mw=164 700 Dalton).

EXAMPLE 3 Preparation of a Random (D,L-lactide/glycolide) Copolymerhaving a Lactide/glycolide Composition Close to 50/50

0.16 g (0.36 mmol) of [(Me₃Si)₂N]₂Sn, 7.87 g (54.7 mmol) of D,L-lactideand 6.34 g (54.7 mmol) of glycolide are introduced successively into aSchlenk tube equipped with a magnetic stirrer and purged under argon.The reaction mixture is left under stirring at 180° C. for 2 hours. NMRanalysis of the proton allows verification that the conversion of eachof the monomers is 100%. The ratio of the signal integrals correspondingto the polylactide part (5.20 ppm) and polyglycolide part (4.85 ppm)allows the composition of the copolymer to be evaluated at 50% lactideand 50% glycolide. According to GPC analysis, using a calibrationcarried out from PS standards with masses 761 to 400 000, this copolymeris a mixture of macromolecules (Mw/Mn=1.7) of high masses (Mw=39 000Dalton).

EXAMPLE 4 Preparation of Another Random (D,L-lactide/glycolide)Copolymer having a Lactide/glycolide Composition Close to 50/50

0.16 g (0.36 mmol) of [(Me₃Si)₂N]₂Sn, 8 g (55 mmol) of D,L-lactide and6.34 g (55 mmol) of glycolide and 25 ml of mesitylene are introducedsuccessively into a Schlenk tube equipped with a magnetic stirrer andpurged under argon. The reaction mixture is left under stirring at 180°C. for 2 hours. NMR analysis of the proton allows verification that theconversion of the monomers is 100% lactide and 100% glycolide. The ratioof the signal integrals corresponding to the polylactide part (5.20 ppm)and polyglycolide part (4.85 ppm) allows of the composition of thecopolymer to be evaluated at 47% lactide and 53% glycolide. According toGPC analysis, using a calibration carried out from PS standards withmasses 761 to 400 000, this copolymer is a mixture of macromolecules(Mw/Mn=1.5) of high masses (Mw=39 400 Dalton).

EXAMPLE 5 Preparation of a Block (D,L-lactide/glycolide) Copolymer

2.0 g (14 mmol) of D,L-lactide, 7 ml of mesitylene and 41 mg (0.09 mmol)of [(Me₃Si)₂N]₂Sn are introduced successively into a Schlenk tubeequipped with a magnetic stirrer and purged under argon. The reactionmixture is left under stirring at 180° C. for 2 hours. NMR analysis ofthe proton allows verification that the conversion of the monomer isgreater than 96%. GPC analysis, using a calibration carried out from PSstandards with masses 761 to 400 000, shows that the polymer is amixture of macromolecules having masses which are close together(Mw/Mn=1.76; Mw=18 940 Dalton). 0.2 g (1.75 mmol) of glycolide is addedto the previous solution maintained under stirring at 180° C. Thereaction mixture is left under stirring at 180° C. for 1 hour. Analysisof an aliquot by NMR of the proton shows that the conversion of theglycolide is total and that a copolymer is formed. The ratio of thesignal integrals corresponding to the polylactide part (5.20 ppm) andpolyglycolide part (4.85 ppm) is 7.3/1. GPC analysis shows that thechains were extended (Mw/Mn=1.89; Mw=21 560 Dalton).

EXAMPLE 6 Preparation of a Random (D,L-lactide/glycolide) Copolymerhaving a Lactide/glycolide Composition in the Region of 50/50

0.08 g (0.11 mmol) of {[(Me₃Si)₂N]Sn(Ot-Bu)}₂, 4.9 g (34 mmol) ofD,L-lactide and 3.9 g (34 mmol) of glycolide and 25 ml of mesitylene areintroduced successively into a Schlenk tube equipped with a magneticstirrer and purged under argon. The reaction mixture is left understirring at 180° C. for 2 hours. NMR analysis of the proton allowsverification that the conversion of the monomers is 100% lactide and100% glycolide. The ratio of the signal integrals corresponding to thepolylactide part (5.20 ppm) and polyglycolide part (4.85 ppm) allows thecomposition of the copolymer to be evaluated at 50% lactide and 50%glycolide. According to GPC analysis, using a calibration carried outfrom PS standards with masses 761 to 400 000, this copolymer is amixture of macromolecules (Mw/Mn=1.71) of high masses (Mw=33 140Dalton).

1. In the process of polymerizing heterocyclic compounds, theimprovement comprising using a polymerization catalyst of the formula

wherein M is tin or germanium; L₁ and L₂ are individually selected fromthe group consisting of -E₁₄(R₁₄)R′₁₄)(R″₁₄)(R′₁₅) and -E₁₆(R₁₆), ortogether form -L′₁-A-L′₂; A is a saturated or unsaturated chaincomprising one, two or three elements of group 14 of the Periodic Table,substituted by one member selected from the group consisting of alkyl,cycloalkyl and aryl, each unsubstituted or substituted with a memberselected from the group consisting of halogen, alkyl, aryl, nitro andcyano; L′₁ and L′₂ are individually selected from the group consistingof -E₁₄(R₁₄)(R′₁₄)-, E₁₅(R₁₅)- and -E₁₆-; E₁₄ is an element of group 14of the Periodic Table; E₁₅ is an element of group 15 of the PeriodicTable; E₁₆ is an element of group 16 of the Periodic Table; R₁₄, R′₁₄,R″₁₄, R₁₅, R′₁₅ and R₁₆ are individually selected from the groupconsisting of hydrogen, alkyl, cycloalkyl and aryl, unsubstituted orsubstituted with a member selected from the group consisting of halogen,aryl, cycloalkyl, aryl, nitro and cyano or -E′₁₄RR′R″-, E′₁₄ is anelement of group 14 of the Periodic Table; R, R′ and R″ are individuallyselected from the group consisting of hydrogen, alkyl, cycloalkyl, andaryl, unsubstituted or substituted by a member selected from the groupconsisting of halogen, alkyl, aryl, nitro and cyano.
 2. The process ofclaim 1 wherein M is tin.
 3. The process of claim 1 wherein L₁ and L₂are individually selected from the group consisting of-E₁₄(R₁₄(R′₁₄)(R″₁₄), -E₁₅(R₁₅)(R′₁₅) and -E,₁₆(R₁₆).
 4. The process ofclaim 1 wherein E₁₄ is carbon or silicon; E₁₅ is nitrogen or phosphorus;E₁₆ is oxygen or sulfur; R₁₄, R′₁₄, R″₁₄, R₁₅ and R₁₆ are individuallyselected from the group consisting of hydrogen, alkyl and E′₁₄RR′R″; E₁₄is carbon or silicon; R, R′ and R″ are individually selected from thegroup consisting of hydrogen or ackyl.
 5. The process of claim 1 whereinL₁ and L₂ are individually -E₁₅(R₁₅)R′₁₅ or -E₁₆(R₁₆); E₁₅ is nitrogen;E₁₆ is oxygen; R₁₅ and R′₁₅ are individually alkyl or -E′₁₄RR′R R₁₆ isalkyl; E′₁₄ is silicon; R, R′ and R″ are individually hydrogen or alkyl.6. The process of claim 1 wherein the compound of formula 1 is-[(Me₃Si₂)N]₂Sn or -{[Me₃Si)₂n]Sn(Ot)Bu)}₂.
 7. The process of claim 1wherein the heterocycle is a cyclic ether.
 8. The process of claim 7wherein the cyclic ether is propylene oxide.
 9. The process of claim 1wherein the heterocycle is a cyclic ester.
 10. The process of claim 1wherein the heterocycle compound is a cyclic ester polyner of lacticacid and/or glycolic acid for obtaining a polymer of lactic acid and/orglycolic acid as the heterocyclic.
 11. In a process for the preparationof block or random copolymers or polymers comprising introducing one ormore heterocyclic monomers, a polymerization catalyst and optionally apolymerization solvent an copolymerizing said monomers, at a temperaturebetween ambient temperature and 250° C., for a duration of a few minutesup to 300 hours, the improvement comprising using as the chain initiatorand the polymerization catalyst having the formula

of claim
 1. 12. The process of claim 11 wherein the one or moreheterocyclic monomers are selected from the group consisting of epoxidesand cyclic esters of lactic and/or glycolic acid.